RU2230744C2 - Tricyclic ?3-piperidines, methods for their preparing and pharmaceutical composition based on thereof - Google Patents

Abstract

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I)

wherein Alk represents (C₁-C₆)-alkanediyl; n = 0 or 1; X represents -O- or -S-; R¹ represents halogen atom, (C₁-C₆)-alkyl or (C₁-C₄)-alkyldioxy-group; D represents radical of formulas (a)

, (b)

, (c)

, (d)

, (e)

, (f)

, (g)

, (h)

, (i)

, (j)

and (k)

. Invention relates also to a method for preparing these compounds and to a pharmaceutical composition used for treatment of diseases with antagonistic activity with respect to central α₂-adrenoceptors. Invention provides preparing new compounds eliciting valuable pharmaceutical properties.

EFFECT: improved preparing methods.

12 cl, 3 tbl, 9 ex

Description

The present invention relates to tricyclic Δ3-piperidines having antagonistic activity towards central α ₂ -adrenoreceptors. It also relates to their preparation, to compositions comprising them, and to their use as medicaments.

Antagonists of central α ₂ -adrenoreceptors are known to increase the release of norepinephrine by blocking presynaptic α ₂ receptors, which exercise inhibitory control over the release of neurotransmitters. Due to their ability to increase the concentration of norepinephrine, α ₂ antagonists can be used in the clinic for the treatment or prevention of depression, cognitive impairment, Parkinson's disease, diabetes mellitus, sexual dysfunction and impotence, increased intraocular pressure and diseases associated with impaired enterokinesis, since all of these conditions are associated with a deficiency of norepinephrine in the central or peripheral nervous system.

The compounds of the present invention are new and have specific and selective binding affinity for various known subtypes of α ₂ -adrenoreceptors, i.e. to α _2A , α _2B and α _2c- adrenoreceptors.

The present invention relates to compounds of the formula

to their N-oxide forms, pharmaceutically acceptable addition salts and stereochemically isomeric forms, where:

Alk is C _1-6 alkanediyl;

n is 1 or 2;

X ₁ represents —O—, —S—, —S (= O) - or —S (= O) ₂ -;

each R ¹ independently represents hydrogen, halogen, C _1-6 alkyl, nitro, hydroxy or C _1-4 alkyloxy;

D represents a radical of the formula

wherein

each m is independently 0, 1 or 2;

X ₂ represents —O— or —NR ¹¹ -;

each X ₃ independently represents —O—, —S— or —NR ¹¹ -;

X ₄ represents —O—, —S—, —CH ₂ —S— or —NR ¹² -;

X ₅ and X ₆ each independently represent —CH ₂ -, —O—, —S— or —NR ¹¹ -;

R ² represents hydrogen, C _1-6 alkyl, aryl or aryl C _1-6 alkyl;

R ³ represents hydrogen, C _1-6 alkyl, C _1-6 alkyloxy, C _1-6 alkylthio, amino or mono- or di (C _1-6 alkyl) amino;

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁵ each independently represents hydrogen or C _1-6 alkyl;

R ¹² represents hydrogen, C _1-6 alkyl, C _1-6 alkyloxyC _1-6 alkyl or pyridinyl C _1-6 alkyl;

R ¹³ , R ¹⁴ and R ¹⁶ each independently represents halogen or C _1-6 alkyl;

R ³ and R ⁴ taken together can form a bivalent radical —R ³ —R ⁴ - formulas

-CH ₂ -CH ₂ -CH ₂ - (a-1)

-CH ₂ -CH ₂ -CH ₂ -CH ₂ - (a-2)

-CH = CH-CH ₂ - (a-3)

-CH ₂ -CH = CH- (a-4) or

-CH = CH-CH = CH- (a-5)

moreover, one or two hydrogen atoms in the aforementioned radicals (a-1) to (a-5) each independently can be substituted with halogen, C _1-6 alkyl, aryl C _1-6 alkyl, trifluoromethyl, amino, hydroxy, C _{1- 6} alkyloxy or C _1-10 alkylcarbonyloxy; or, when possible, two geminal hydrogen atoms may be substituted with C _1-6 alkylidene or aryl C _1-6 alkylidene; or

-R ³ -R ⁴ - may also represent

-S-CH ₂ -CH ₂ - (a-6)

-S-CH ₂ -CH ₂ -CH ₂ - (a-7)

-S-CH = CH- (a-8)

-NH-CH ₂ -CH ₂ - (a-9)

-NH-CH ₂ -CH ₂ -CH ₂ - (a-10)

-NH-CH = CH- (a-11)

-NH-CH = N- (a-12)

-S-CH = N- (a-13) or

-CH = CH-O- (a-14)

one or, when possible, two or three hydrogen atoms in said radicals (a-6) to (a-14) each independently may be substituted with C _1-6 alkyl or aryl; and

aryl is phenyl or phenyl substituted with one, two or three substituents selected from halogen, hydroxy, nitro, cyano, trifluoromethyl, C _1-6 alkyl, C _1-6 alkyloxy, C _1-6 alkylthio, mercapto, amino, mono and di (C _1-6 alkyl) amino, carboxyl, C _1-6 alkyloxycarbonyl and C _1-6 alkylcarbonyl.

Used in the above definitions, the term halogen combines fluorine, chlorine, bromine and iodine. The term C _1-4 alkyl means linear and branched saturated hydrocarbons having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, etc. P. The meanings of the term C _1-6 alkyl include C _1-4 alkyl radicals and their higher homologues having 5 or 6 carbon atoms, such as, for example, pentyl, hexyl and the like. The meanings of the term C _1-10 alkyl include C _1-6 alkyl radicals and their higher homologues having from 7 to 10 carbon atoms, such as, for example, heptyl, octyl, nonyl, decyl and the like. The term “C _1-5 alkanediyl” means straight or branched chain bivalent alkanediyl radicals having from 1 to 5 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1 5-pentanediyl and the like. The term C _1-6 alkanediyl is meant to include C _1-5 alkanediyl and its higher homologue having 6 carbon atoms, such as, for example, 1,6-hexanediyl and the like. The term C _1-6 alkylidene means straight or branched chain bivalent alkylidene radicals having from 1 to 6 carbon atoms, such as, for example, methylene, ethylidene, 1-propylidene, 1-butylidene, 1-pentylidene, 1-hexylidene, and t .P.

The term addition salts is meant to include therapeutically active forms of the addition salts which (the compounds of formula (I)) are capable of forming with appropriate acids, such as, for example, inorganic acids, such as hydrohalic acids, for example hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and other acids; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, fumaric, malic, tartaric, citric, methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesulphonic aminocyl, cyclic pamova and other acids.

The term pharmaceutically acceptable addition salts, as mentioned hereinabove, is also intended to include the forms of the addition salts with a therapeutically active non-toxic base, in particular a metal or amine, which are capable of forming compounds of formula (I). Said salts can be easily obtained by treating compounds of formula (I) containing acidic hydrogen atoms with appropriate organic or inorganic bases, salts such as, for example, ammonium salts, alkali and alkaline earth metal salts, for example, lithium, sodium, potassium salts, magnesium, calcium, etc., salts of organic bases, for example, benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids, such as, for example, arginine, lysine, etc.

Conversely, said salt forms can be converted into the free forms of acids or bases by treatment with an appropriate base or acid.

The term addition salt, as used hereinabove, also includes solvates that the compounds of formula (I) are capable of forming, and it is intended that said solvates be included within the scope of the present invention. Examples of such solvates are, for example, hydrates, alcoholates, and the like.

N-oxide forms of compounds of formula (I) include those compounds of formula (I) in which one or more nitrogen atoms are oxidized to the so-called N-oxide.

The term stereochemically isomeric forms in this document refers to all possible isomeric forms in which the compounds of formula (I) can be present. Unless otherwise specified or otherwise specified, the chemical designation of the compounds means a mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure.

Some of the compounds of formula (I) may also exist in tautomeric forms. It is understood that such forms, although not clearly indicated in the above formula, are included within the scope of the present invention.

Further, when reference is made to the position of the substituent R ¹ , the following numbering is used:

It is understood that wherever it is used in this document, the term compounds of formula (I) also includes N-oxide forms, pharmaceutically acceptable addition salts and all stereoisomeric forms.

Particular compounds are those compounds of formula (I) in which D represents a radical of formula (a), (b), (c), (d), (e), (f), (g), (h), (i ), (j), (k) or (l); m is 0; and aryl is phenyl, or phenyl substituted with halogen or C _1-6 alkyl.

Compounds worthy of attention are those compounds of formula (I) in which n is 1 and R ¹ is hydrogen, chloro, fluoro, methyl, methoxy or nitro, especially when R ¹ is hydrogen, chloro, methyl or methoxy.

In the event that R ¹ is different from hydrogen, then R ^{1 is} suitably bonded to the tricyclic ring system in the 6 or 7 position.

Another group of compounds of interest are those compounds of formula (I) in which Alk is methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl or 1,5-pentanediyl.

The next group of compounds of interest are compounds of formula (I) in which D is a radical of formula (a) in which R ² is aryl or methyl, and R ³ and R ⁴ taken together form a bivalent radical of formula (a- 5) or (a-8); or D represents a radical of formula (b) in which R ⁵ and R ⁶ are C _1-6 alkyl, preferably R ⁵ and R ⁶ are methyl; or D represents a radical of formula (c) in which R ⁷ represents hydrogen; or D represents a radical of formula (d) in which X ₂ represents NR ¹¹ - and R ¹¹ represents hydrogen; or D represents a radical of formula (e); or D represents a radical of formula (f) in which X ₃ is —S— and R ⁸ is hydrogen or C _1-6 alkyl, preferably R ⁸ is methyl; or D is a radical of formula (g) in which X ₄ is —CH ₂ —S— or —NR ¹² - and R ¹² is C _1-6 alkyloxyC _1-6 alkyl or pyridinyl C _1-6 alkyl, preferably R ¹² represents ethyloxyethyl or pyridinylmethyl; or D represents a radical of formula (h) in which X ₅ is —O— or —S—, and R ¹⁰ is hydrogen; or D represents a radical of formula (j); or D represents a radical of formula (k), in which m is preferably 1, and R ¹³ represents halogen.

Particular compounds are those compounds of formula (I) wherein X ₁ is —O— or —S—.

Preferred compounds are those compounds of formula (I) wherein n is 1, R ¹ is hydrogen, chloro, fluoro, methoxy or methyl, X ₁ is —O— or —S—, and D is a radical of formula (a), ( b), (c), (d), (e), (f), (g), (h), (i), (j) or (k).

More preferred compounds are compounds of formula (I) in which D is a radical of formula (a), (c), (d), (f) and (h); X ₁ represents O or S; n is 1; R ¹ represents hydrogen, halogen or methyl, and is a substituent in the 6 position; and Alk is 1,2-ethanediyl, 1,3-propanediyl or 1,4-butanediyl.

The most preferred compounds are the compounds shown below, or their N-oxide forms, pharmaceutically acceptable addition salts and stereochemically isomeric forms.

Typically, compounds of formula (I) can be prepared by N-alkylating an intermediate of formula (II) with an alkylating reagent of formula (III), following the procedure described in EP-A-0037265, EP-A-0070053, EP-A-0196132 and EP -A-0378255. In particular, N-alkylation can be carried out in a reaction inert solvent, such as, for example, methyl isobutyl ketone, N, N-dimethylformamide or N, N-dimethylacetamide, in the presence of a base, for example triethylamine, sodium carbonate or sodium bicarbonate, and optionally in the presence of a catalyst, such as potassium iodide.

In intermediate (III), W ¹ represents a suitable reactive leaving group, such as halogen, for example, chlorine, bromine or iodine; sulfonyloxy, e.g. methanesulfonyloxy, 4-methylbenzenesulfonyloxy.

In this and the following reactions, reaction products can be isolated from the reaction medium and, if necessary, further purified in accordance with methods well known in the art, such as extraction, crystallization, trituration and chromatography.

Compounds of formula (I) in which D represents a radical of formula (f) represented by formula (If) can be prepared by N-alkylating an amine of formula (IV) with intermediate (V), in which W ² represents a suitable reactive leaving group, such such as halogen.

A representative process for the preparation of compounds of formula (I) wherein D is a radical of formula (j) and Alk is - (Alk ′) _p —CH ₂ -, where Alk ′ is C _1-5 alkanediyl and p is 0 or 1 , i.e. compounds represented by formula (Ij) includes reductive N-alkylation of an intermediate of formula (II) with an aldehyde derivative of formula (IV).

Said reductive N-alkylation reaction may conveniently be carried out by reducing a mixture of reactants in a suitable solvent inert to the reaction, following the techniques known in the art for reductive N-alkylation. In particular, to increase the reaction rate, the reaction mixture can be stirred and / or heated. Suitable solvents are, for example, water, methanol, ethanol, 2-propanol and the like. The reaction is conveniently carried out using sodium cyanoborohydride, sodium borohydride, formic acid, or their salts, and similar reducing agents, or, alternatively, in a hydrogen atmosphere, optionally at elevated temperature and / or pressure, in the presence of a suitable catalyst, such as, for example, palladium on charcoal, platinum on charcoal, etc. To prevent undesired additional hydrogenation of certain functional groups in the reactants and reaction products, it may be useful to add a suitable agent, a poisoning catalyst, for example, thiophene, quinoline-sulfur, etc. to the reaction mixture. In some cases, it may also be useful to add an alkali metal salt to the reaction mixture, such as, for example, potassium fluoride, potassium acetate and the like.

The compounds of formula (I) can be converted into each other using functional group conversion reactions known in the art.

The compounds of formula (I) can also be converted into the corresponding N-oxide forms using methods known in the art for converting trivalent nitrogen to its N-oxide form. Typically, said N-oxidation reaction can be carried out by reacting a starting material of formula (I) with an appropriate organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides, for example, sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxy acids, such as, for example, benzene carboxy peroxy acid, or a halogen-substituted benzene carboxy peroxy acid, for example 3-chlorobenzene carboxy peroxy acid, peroxyalkanoic acids, for example, peroxyacetic acid, alkyl hydroperoxides, for example tert-butyl peroxides. Suitable solvents are, for example, water, lower alkanols, for example ethanol and the like, hydrocarbons, for example toluene, ketones, for example 2-butanone, halogenated hydrocarbons, for example dichloromethane, and mixtures of such solvents.

A number of intermediates and starting materials are commercially available, or are known compounds that can be prepared according to methods known in the art.

For example, some of the intermediates of formula (III) and methods for their preparation are described in EP-A-0037265, EP-A-0070053, EP-A-0196132 and EP-A-0378255.

Intermediates of formula (II) in which X is —O— can be prepared as described in Syn. Comm. (1995), pp. 3883-3900 and J. Chem. Soc., 1965, pp. 4939-4953; and using methods known in the art. The general methodology is depicted in diagram 1.

Scheme 1

Intermediates of formula (II) in which X is —S— can be prepared according to J. Med. Chem., 1992, 35 (7), pp. 1176-1182, and using methods known in the art. . The general methodology is depicted in diagram 2.

Scheme 2

Альтернативно, промежуточные соединения формулы (II) могут быть получены в соответствии с Synth. Comm., 1995, стр.3883-3900, и с помощью методов, известных в данной области. Общая методика изображена на схеме 3.

Alternatively, intermediates of formula (II) may be prepared according to Synth. Comm., 1995, pp. 3883-3900, and using methods known in the art. The general methodology is depicted in diagram 3.

Scheme 3

Intermediates of formula (III) in which D represents a radical of formula (h) represented by formula (III-h) can be prepared by reacting a benzisoxazole or benzisothiazole of formula (VII) in which W ³ represents a suitable leaving group, such as, halogen, with an amino alcohol derivative of the formula (VIII), in the presence of a catalyst such as potassium iodide. Typically, the reaction mixture is stirred at elevated temperatures. Subsequently, a suitable leaving group, such as halogen, for example chlorine, can be introduced into the alcohol derivative thus obtained using methods known in the art, for example, the reaction of an alcohol with thionyl chloride in a solvent such as chloroform.

Some compounds of formula (I) and some intermediates of the present invention contain at least one asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained using procedures known in the art. For example, diastereomers can be separated using physical methods, such as selective crystallization or chromatographic techniques, for example, countercurrent distribution, liquid chromatography, and the like. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures using suitable resolving agents, such as, for example, chiral acids, into a mixture of diastereomeric salts or compounds; then the physical separation of these mixtures of diastereomeric salts or compounds using, for example, selective crystallization or chromatographic techniques, for example, liquid chromatography and similar methods; and finally, the conversion of the aforementioned separated diastereomeric salts or compounds into the corresponding enantiomers.

Pure stereochemically isomeric forms of the compounds of formula (I) can also be obtained from pure stereochemically isomeric forms of the corresponding intermediates and starting materials, provided that the intermediate reactions occur stereospecifically. It should be borne in mind that pure and mixed stereochemically isomeric forms of the compounds of formula (I) are included within the scope of this invention.

The compounds of formula (I), their N-oxides, pharmaceutically acceptable addition salts and stereochemically isomeric forms block presynaptic α ₂ receptors on central noradrenergic neurons, thereby increasing the release of norepinephrine. Blocking said receptors suppresses or alleviates a number of symptoms associated with a deficiency of norepinephrine in the central or peripheral nervous system. Therapeutic indications for the use of the compounds of the present invention are depression, cognitive impairment, Parkinson's disease, diabetes mellitus, sexual dysfunction and impotence, as well as increased intraocular pressure.

Blocking of α ₂ receptors in the central nervous system has also been shown to increase the release of serotonin, which may contribute to the therapeutic effect in depression (Maura et al., 1992, Naunyn-Schmiedeberg's Arch. Pharmacol., 345: 410-416).

It has also been shown that blocking α ₂ receptors can cause an increase in the concentration of extracellular DOPAC (3,4-dihydrophenylacetic acid), which is a metabolite of dopamine and norepinephrine.

In view of the usefulness of the subject compounds for treating diseases associated with a central nervous system deficiency of norepinephrine, in particular depression and Parkinson’s disease, the present invention provides a method for treating warm-blooded animals suffering from such diseases, in particular depression and Parkinson’s disease, said method comprising systemic administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.

The compounds of the present invention are also potentially useful for the treatment of Alzheimer's disease and dementia, as it is known that α ₂ antagonists promote the release of acetylcholine (Tellez et al., 1997, J. Neurochem. 68: 778-785).

In general, it is contemplated that a daily effective therapeutic amount is from about 0.01 mg / kg to 4 mg / kg body weight.

Thus, the present invention also relates to compounds of formula (I) as defined hereinabove for use as medicaments. Further, the present invention also relates to the use of compounds of formula (I) in the manufacture of medicaments for the treatment of depression or Parkinson's disease.

Ex vivo and in vitro studies of receptor signal transduction and receptor binding can be used to evaluate the α ₂ adrenergic receptor antagonism of the present compounds. In vivo, restoration of the loss of the rectification reflex in rats observed after intravenous injection of xylazine and inhibition of tremor caused by reserpine in rats can be used as indicators of the blockade of the central α ₂ -adrenoreceptor in vivo.

The compounds of the present invention also have the ability to quickly penetrate the central nervous system.

For the purpose of administration, the subject compounds can be converted into various formulations of pharmaceutical compositions comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound of formula (I). To obtain the pharmaceutical compositions of this invention, an effective amount of a particular compound in the form of an additive salt or free acid or base form as an active ingredient is combined in a intimate mixture with a pharmaceutically acceptable carrier, which can take a wide variety of forms, depending on the form of preparation required for administration. Preferably, these pharmaceutical compositions are presented in unit dosage form, preferably suitable for oral, transdermal, or parenteral injection. For example, in the preparation of compositions in dosage forms for oral administration, any of the usual pharmaceutical media may be used, such as, for example, water, glycols, oils, alcohols, and the like. in the case of liquid preparations for oral administration, such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Due to the ease of administration, tablets and capsules represent the most advantageous single unit dosage forms for oral administration, in which case solid pharmaceutical carriers are obviously employed. In the case of compositions for parenteral administration, the carrier usually includes sterile water, at least it makes up a large part, although other components, for example, promoting solubility, may be included. For example, injection solutions may be prepared in which the carrier comprises saline or saline, glucose, or a mixture of these solutions. Injectable solutions containing the compounds of formula (I) can be prepared in oil to provide a sustained action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic esters of glycerol and long chain fatty acids, and mixtures of these and other oils. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. In compositions suitable for transdermal administration, the carrier optionally includes a penetration enhancing agent and / or a suitable moisturizing agent, optionally in combination with suitable additives of any nature in small amounts, these additives should not have any harmful effects on the skin. Said additives may facilitate administration to the skin and / or may be useful in preparing the desired compositions. These compositions may be administered in various ways, for example, as a transdermal patch, patch, or as an ointment. Additive salts of the compounds of formula (I), due to their increased solubility in water compared to the corresponding free basic or free acid forms, are obviously more suitable in the preparation of aqueous compositions.

Particularly advantageous is the preparation of the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The unit dosage form in the description and claims of this document refers to physically discrete units suitable as unit doses, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including notched tablets and coated tablets), capsules, pills, powder sachets, cachets, injectable solutions or suspensions, containers in a teaspoon, tablespoon and the like, and multiple thereof forms.

The following examples are intended to illustrate the present invention.

experimental part

Hereinafter, the term CT refers to room temperature, THF refers to tetrahydrofuran, and DIPE refers to diisopropyl ether.

Preparation of Intermediates

Example A1

a) A mixture of 3-chloro-1,2-benzisoxazole (0.08 mol), 4-amino-1-butanol (0.24 mol) and KI (1 g) was stirred for 4 days at 80 ° C. The reaction mixture was cooled, dissolved in CH ₂ Cl ₂ and purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH 95/5). Pure fractions were collected and the solvent was evaporated, yielding 15.4 g (93%) of 4- (1,2-benzisoxazol-3-ylamino) -1-butanol (interm. 1).

b) Thionyl chloride (0.048 mol) is cooled to 0 ° C. A solution of intermediate 1 (0.048 mol) in CHCl ₃ (20 ml) was added dropwise and the reaction mixture was stirred overnight at RT. The solvent was evaporated. The residue is washed with water. The reaction mixture was extracted with CH ₂ Cl ₂ . The separated organic layer was dried (MgSO ₄ ), filtered and the solvent was evaporated, yielding 10.4 g of N- (4-chlorobutyl) -1,2-benzisoxazole-3-amine (interm. 2).

Example A2

a) The reaction takes place in an atmosphere of N ₂ . NaH 60% (0.17 mol) was stirred in THF (350 ml). A solution of diethyl (cyanomethyl) phosphonate (0.17 mol) in THF (150 ml) was added dropwise over ± 20 min (exothermic increase in temperature to 30 ° C). The mixture is stirred for 20 minutes at RT, then cooled to 0 ° C. A solution of 5-methyl-3-benzofuranone (0.15 mol) in THF (350 ml) was added dropwise over 30 minutes at 0 ° C. The reaction mixture was stirred overnight at RT, then poured into water (1500 ml) and stirred. The mixture was extracted with ether, DIPE (2 ×), dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / hexane 50/50). The desired fractions were collected and the solvent was evaporated, yielding 21.2 g (82%) of 5-methyl-3-benzofuranacetonitrile (interm. 3).

b) A mixture of intermediate (3) (0.12 mol) in NH ₃ / CH ₃ OH (400 ml) was hydrogenated using Raney nickel (3 g) as a catalyst. After uptake of H ₂ (2 equiv.), The catalyst was filtered off and the filtrate was evaporated. The residue was purified on silica gel on a glass filter (eluent: CH ₂ Cl ₂ / (CH ₃ OH / NH ₃ ) 98/2 to 96/4). The desired fractions were collected and the solvent was evaporated. The residue (± 2.1 g) was dissolved in 2-propanol (500 ml) and converted to the hydrochloric acid salt (1: 1) using HCl / 2-propanol. The mixture was stirred at RT. The solvent was evaporated. The residue was stirred in DIPE, filtered and dried, yielding 24.4 g (96%) of 5-methyl-3-benzofuranethanamine hydrochloride (1: 1) (interm. 4).

c) A mixture of intermediate (4) (0.0024 mol) in H ₂ O (2 ml), acetic acid (2 ml) and 37% formaldehyde (2 ml) was stirred for one hour at 100 ° C. The reaction mixture was cooled and poured into 1M NaOH (50 ml). The precipitate was filtered off, washed with water, then dissolved in 1N HCl (100 ml). The mixture is stirred for 15 minutes in a heated water bath (80 ° C). The solvent was evaporated. 2-propanol is added. The solvent was evaporated. The residue was stirred in boiling 2-propanone, then allowed to cool to RT with stirring. The precipitate was filtered off and dried, yielding 0.40 g of 1,2,3,4-tetrahydro-6-methylbenzofuro [2,3-c] pyridine monohydrochloride. monohydrate (interm. 5).

Example A3

a) A mixture of 1,2,3,4-tetrahydro- [1] benzothieno [2,3-c] pyridine (0.02 mol), Na ₂ CO ₃ (5 g), KI (0.1 g) and 4 -chlorobutanenitrile (0.025 mol) in acetonitrile (50 ml) and methylbenzene (150 ml) was stirred and refluxed overnight, then cooled, filtered and the filtrate was evaporated. The residue (oil) was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH 98/2). Pure fractions were collected and the solvent was evaporated, yielding 5.2 g of 3,4-dihydrobenzothieno [2,3-c] pyridin-2 (1H) -butanenitrile (interm. 6).

b) A mixture of intermediate (6) (0.0195 mol) in NH ₃ / CH ₃ OH (200 ml) was hydrogenated using Raney nickel (4 g) as a catalyst in the presence of a thiophene solution (4 ml). After uptake of H ₂ (2 equiv.), The catalyst was filtered off through dicalite and the filtrate was evaporated, yielding 3.9 g of 3,4-dihydrobenzothieno [2,3-c] pyridin-2 (1H) -butanamine (interm. 7).

Example A4

a) A mixture of 6-chloro-1,2,3,4-tetrahydro [1] benzothieno [2,3-c] pyridine (0.02 mol), 1,1-dimethylethyl (4-chlorobutyl) carbamate (0.02 mol), Na ₂ CO ₃ (3.5 g) and KI (0.1 g) in 4-methyl-2-pentanone (300 ml) were stirred and heated under reflux overnight. The reaction mixture was cooled, filtered and the filtrate was evaporated. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH 96/4). The desired fractions were collected and the solvent was evaporated, yielding 5.2 g of 1,1-dimethylethyl [4- (6-chloro-3,4-dihydrobenzo [1] thieno [2,3-c] pyridin-2 (1H) -yl) butyl] carbamate (interm. 8).

b) A mixture of intermediate (8) (0.013 mol) in HCl / 2-propanol (50 ml) and 2-propanol (100 ml) was stirred and heated under reflux for 30 minutes. The reaction mixture is cooled. The precipitate (HCl salt) is filtered off and converted to the free base using NH ₄ OH. The mixture was extracted with CH ₂ Cl ₂ . The separated organic layer was dried, filtered and the solvent was evaporated. The residue was triturated with CH ₃ CN / DIPE, filtered and dried, yielding 2.2 g of 6-chloro-3,4-dihydrobenzo [1] thieno [2,3-c] pyridin-2 (1H) -yl) butanamine (interm. Comp. 9).

Example A5

a) A mixture of 37% formaldehyde (31 g) and ZnCl ₂ (10 g) in ethyl acetate (90 ml) and 12N Hcl (190 ml) was stirred at -10 ° C. HCl (gaseous) is allowed to bubble through the mixture until saturated (at -10 ° C). At a temperature <0 ° C, 5-fluorobenzo [b] thiophene (0.35 mol) is added dropwise. The reaction mixture was stirred overnight at room temperature. Toluene (200 ml) was added and the mixture was vigorously stirred. The organic layer was separated, washed with an aqueous solution of NaHCO ₃ and water, dried, filtered and the solvent was evaporated. The residue was triturated in hexane, filtered and dried, yielding 58 g of 3- (chloromethyl) -5-fluorobenzo [b] thiophene (82.6%) (interm. 10).

b) A mixture of sodium cyanide (0.33 mol) and octahydrodibenzo [b, k] [1,4,7,10,13,16] hexaoxacyclooctadecin (0.050 g) in dimethyl sulfoxide (110 ml) was stirred at 30 ° C. Intermediate (10) (0.29 mol) is added over 30 minutes. The mixture was allowed to cool to room temperature with stirring. Then the reaction mixture is stirred in ice water. The precipitate was filtered off, washed with water and dissolved in CH ₂ Cl ₂ . The organic solution was dried, filtered and the solvent was evaporated, yielding 5-fluorobenzo [b] thiophene-3-acetonitrile (interm. 11).

c) A mixture of intermediate (11) (0.29 mol) in NH ₃ / CH ₃ OH (700 ml) was hydrogenated at 14 ° C. using Raney nickel (5 g) as a catalyst in the presence of a solution of thiophene (10 ml). After uptake of H ₂ (2 equiv.), The catalyst was filtered off through dicalite and the filtrate was evaporated. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / (CH ₃ OH / NH ₃ ) 96/4). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in DIPE and converted to the hydrochloric acid salt (1: 1) using HCl / 2-propanol. The precipitate was filtered off, washed with DIPE and dried, yielding 48.5 g of 5-fluorobenzo [b] thiophen-3-ethanamine hydrochloride (1: 1) (interm. 12).

d) A mixture of intermediate (12) (0.21 mol) in H ₂ O (190 ml), acetic acid (190 ml) and 37% formaldehyde (190 ml) was stirred and heated under reflux for one hour. The reaction mixture was allowed to cool to room temperature, then poured into 4N NaOH (1200 ml) with stirring. The precipitate is filtered off and triturated in CH ₃ CN, filtered off, washed with DIPE and dried, yielding 21 g of 1,1'-methylenebis [6-fluoro-1,2,3,4-tetrahydro [1] benzothieno [2,3- c] pyridine (interm. 13).

e) A mixture of intermediate (13) (0.049 mol) in water (1700 ml) and 12N Hcl (285 ml) was stirred and heated under reflux for one hour. The precipitate was filtered off, washed with CH ₃ CN and DIPE and dried, yielding 17.7 g of 6-fluoro-1,2,3,4-tetrahydro [1] benzothieno [2,3-c] pyridine hydrochloride (interm. 13 )

Example A6

The reaction takes place in an atmosphere of N ₂ . A solution of 1,2-dichloroethanedioyl (0.026 mol) in CH ₂ Cl ₂ (60 ml) was stirred at -60 ° C. Dimethyl sulfoxide (3.8 ml) was added dropwise at -60 ° C and the mixture was stirred for 10 minutes. A solution of intermediate (1) (0.024 mol) in CH ₂ Cl ₂ (120 ml) was added dropwise at -60 ° C and the mixture was stirred for one hour at -60 ° C. N, N-diethylethanamine (13.7 ml) was added dropwise and the reaction mixture was stirred for 10 minutes at -60 ° C, after which it was allowed to warm to room temperature. The mixture was poured into water (250 ml). The mixture is stirred for 10 minutes. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was triturated in hexane, filtered and dried, yielding 3.9 g of 4- (1,2-benzisoxazol-3-ylamino) butanal (80%) (interm. 15).

B. Preparation of target compounds

Example B1

a) A mixture of 1,2,3,4-tetrahydrobenzofuro [2,3-c] pyridine hydrochloride (1: 1) (0.007 mol), 3- (2-chloroethyl) -2-methyl-4H-pyrido [1,2 -a] -pyrimidin-4-one (0.012 mol), Na ₂ CO ₃ (0.015 mol) and KI (catalytic amount) in 2-butanone (100 ml) were stirred and heated under reflux overnight. The reaction mixture was filtered hot and the filtrate was evaporated. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / (CH ₃ OH / NH ₃ ) 98/2 to 97/3). The purest fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and (E) -2-butenedioic acid (1 g) was added. The mixture is boiled and then stirred at RT. The precipitate was filtered off and dried, yielding 2.00 g (61%) of 3- [2- (3,4-dihydrobenzofuro [2,3-c] pyridin-2 (1H) -yl) ethyl] -2-methyl-4H- pyrido [1,2-a] pyrimidin-4-one (E) -2-butene-dioate (2: 1) (compound 1).

Example B1b

A mixture of 6-chloro-1,2,3,4-tetrahydro [1] benzothieno [2,3-c] pyridine hydrochloride (1: 1) (0.01 mol), 1- (4-chlorobutyl) -1, 3-dihydro-3- (1-methylenethenyl) -2H-benzimidazol-2-one (0.01 mol), Na ₂ CO ₃ (3.5 g) and KI (0.1 g) in 2-butanone (200 ml) was stirred and heated under reflux overnight, then cooled, filtered and the filtrate was evaporated. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / (CH ₃ OH / NH ₃ ) 95/5). The desired fractions were collected and the solvent was evaporated. The residue was stirred in a boiling mixture of HCl / 2-propanol. DIPE is added and the mixture is stirred. The precipitate was filtered off, washed with DIPE and dried. This fraction is converted to the free base, then extracted with CH ₂ Cl ₂ . The separated organic layer was dried, filtered and the solvent was evaporated. The residue was dissolved in 2-propanone and converted into the salt of (E) -2-butenedioic acid (1: 1). The precipitate was filtered off, washed with DIPE and dried, yielding 0.82 g of 1- [4- (6-chloro-3,4-dihydrobenzothieno [2,3-c] pyridin-2 (1H) -yl) butyl] -1.3 -dihydro-2H-benzimidazol-2-one (E) -2-butenedioate (1: 1) (compound 21).

Example B2

A mixture of 6-chloro-1,2,3,4-tetrahydro [1] benzothieno [2,3-c] pyridine hydrochloride (1: 1) (0.00057 mol), 7- (2-chloroethyl) -1, 3-Dimethyl-7H-purine-2,6- (1H, 3H) -dione (0,100 g) and Na ₂ CO ₃ (0,100 g) in 2-butanone (2 ml) are stirred over the weekend at 100 ° C. The target compound is isolated and purified by high performance liquid chromatography on Kromasil unmodified silica gel with spherical particles (55 g, 60A, 5 μm) (column: 2 cm ID; eluent: CH ₂ Cl ₂ / (CH ₂ Cl ₂ / CH ₃ OH 90/10) / CH ₃ OH (0 min) 100/0/0, (10.50 min) 0/100/0, (12.50 min) 50/0/50, (14.00 min) 0 / 0/100, (15.01-20.00 min) 100/0/0). Pure fractions were collected and the solvent was evaporated, yielding 0.070 g of 7- [2- (3,4-dihydrobenzothieno [2,3-c] pyridin-2 (1H) -yl) ethyl] -1,3-dimethyl-1H-purine -2.6 (3H, 7H) dione (compound 7).

Example B3

A mixture of intermediate (9) (0.007), 2-chlorobenzothiazole (0.01 mol) and Na ₂ CO ₃ (2 g) in 2-ethoxyethanol (50 ml) was stirred and refluxed for 3 hours. The reaction mixture was cooled filtered and the filtrate evaporated. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH 96/4). Pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE / CH ₃ CN, filtered off, washed with DIPE and dried, yielding 1.75 g of N-2-benzothiazolyl-6-chloro-3,4-dihydrobenzo [1] thieno [2,3-c] pyridin-2 (1H) -butanamine (58.3%) (compound 64).

Example B4

A mixture of 3,4-dihydro-7-methoxybenzofuro [2,3-c] pyridin-2 (1H) -butanamine (0.0055), 3-chloro-1,2-benzisothiazole (0.0089 mol) and NaHCO ₃ ( 0.01 mol) was stirred for 1.5 hours at 120 ° C (melt). 1-butanol (0.5 ml) was added. The reaction mixture was cooled, then dissolved in CH ₂ Cl ₂ and purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / (CH ₃ OH / NH ₃ ) 98/2). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanone and converted to the hydrochloric acid salt (1: 2) using HCl / 2-propanol. The mixture was stirred at room temperature. The precipitate was filtered off and dried, yielding 1.60 g of N- (1,2-benzisothiazol-3-yl) -3,4-dihydro-7-methoxybenzofuro [2,3-c] pyridin-2 (1H) -butanamine monohydrochloride monohydrate (61%) (compound 55).

Example B5

Acetic acid (0.005 mol) was added to 1,2,3,4-tetrahydro-7-methoxybenzofuro [2,3-c] pyridine monohydrate monohydrate (0.005 mol) in 1,2-dichloroethane (30 ml). Intermediate (15) (0.005 mol) was added and the mixture was stirred until complete dissolution. NaBH (OAc) ₃ (0.005 mol) was added and the reaction mixture was stirred over the weekend at room temperature. The reaction mixture was diluted with CH ₂ Cl ₂ (100 ml), washed with 10% aqueous NaOH, then dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / (CH ₃ OH / NH ₃ ) 98/2). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanone and converted into the salt of (E) -2-butenedioic acid (2: 1) using (E) -2-butenedioic acid (0.8 g). The mixture is boiled, then left to cool to room temperature with stirring. The precipitate was filtered off and dried, yielding 1.50 g of N- (1,2-benzisoxazol-3-yl) -3,4-dihydro-7-methoxybenzofuro [2,3-c] pyridin-2 (1H) -butanamine (68 %) (compound 65).

Example B6

A mixture of intermediate (7) (0.015 mol), 2-chlorobenzothiazole (0.015 mol), Na ₂ CO ₃ (3 g) and KI (catalytic amount) in methylbenzene (150 ml) was stirred and refluxed overnight, then cooled to 50 ° C. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / CH ₃ OH 95/5). Pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH ₃ CN, filtered and dried, yielding 2.4 g of N-2-benzothiazolyl-3,4-dihydrobenzothieno [2,3-c] pyridin-2 (1H) -butanamine (compound 25).

Example B7

The 1,2,3,4-tetrahydrobenzofuro [2,3-c] pyridine hydrochloride (1: 1) (0.01 mol) was converted to the free base using CH ₂ Cl ₂ / H ₂ O · NH ₄ OH. A mixture of the above free base, intermediate (2) (0.019 mol) and triethylamine (0.015 mol) in N, N-dimethylacetamide (50 ml) was stirred at 70 ° C. for 48 hours. The solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / (CH ₃ OH / NH ₃ ) 98/2). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and treated with (E) -2-butenedioic acid (1 g). The mixture is boiled, then stirred at RT. The solvent was evaporated. The residue was dissolved in 2-propanone, boiled and then stirred at RT. The solvent was evaporated. The residue was dissolved in 2-propanol, acidified with HCl / 2-propanol, stirred, and the resulting precipitate was filtered off and dried, yielding 0.70 g (16%) of N-1,2-benzisoxazol-3-yl-3,4-dihydrobenzofuro monohydrochloride [2,3-c] pyridin-2 (1H) -butanamine (61%) (compound 36).

Example B8

The starting material 1,2,3,4-tetrahydrobenzofuro [2,3-c] pyridine hydrochloride (1: 1) (0.01 mol) was made basic, extracted and the solvent was evaporated, yielding the free base (1.4 g, 0.008 mol) . A mixture of the above free base and 4-phenoxybenzaldehyde (0.01 mol) in methanol (150 ml) was hydrogenated using 10% Pd / C (1 g) as a catalyst in the presence of 4% thiophene (1 ml). After uptake of H ₂ (1 equiv.), The catalyst was filtered off and the filtrate was evaporated. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / (CH ₃ OH / NH ₃ ) 98/2). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and converted to the salt of (E) -2-butenedioic acid (1: 1) using (E) -2-butenedioic acid (1.2 g). The mixture is boiled, then left to cool to RT with stirring. The precipitate was filtered off and dried, yielding 1.80 g (49%) of 1,2,3,4-tetrahydro-2 - [(4-phenoxyphenyl) methyl] benzofuro [2,3-c] pyridine (E) -2-butenedioate (1: 1) (compound 33).

Example B9

A mixture of 1,2,3,4-tetrahydro [1] benzothieno [2,3-c] pyridine hydrochloride (1: 1) (0.01 mol) and phenoxybenzaldehyde (0.01 mol) in methanol (150 ml) is hydrogenated at 50 ° C using 10% Pd / C (1 g) as a catalyst in the presence of potassium acetate (2 g) and 4% thiophene (1 ml). After uptake of H ₂ (1 equiv.), The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from CH ₃ CN, filtered off and evaporated. This fraction (3 g) was stirred in water with a small amount of NH ₄ OH and the mixture was extracted with CH ₂ Cl ₂ . The separated organic layer was dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was crystallized from CH ₃ CN, filtered and dried, yielding 2.7 g of 1,2,3,4-tetrahydro-2 - [(4-phenoxyphenyl) methyl] benzothieno [2,3-c] pyridine (compound 34).

Table 1 lists the compounds of formula (I), which were obtained in accordance with one of the above examples.

C. Pharmacological examples

Example C.1: In vitro Binding Affinity for α ₂ Receptors The interaction of compounds of formula (I) with α ₂ receptors was evaluated in vitro experiments on the binding of radiolabeled ligands.

Typically, a low concentration of radiolabeled ligand with a high binding affinity for a particular receptor is incubated with a sample of tissue preparation enriched in a specific receptor, or with a preparation of cells expressing cloned human receptors in a buffer medium. During the incubation process, the radiolabeled ligand binds to the receptor. Upon reaching equilibrium of binding, receptor-bound radioactivity is separated from unbound radioactivity, and receptor-bound activity is calculated. The interaction of the test compounds with the receptor is evaluated in competitive binding experiments. Different concentrations of the test compound are added to the incubation mixture containing the receptor preparation and the radiolabeled ligand. The binding of the radiolabeled ligand is inhibited by the test compound in proportion to its binding affinity and concentration.

3H-rauwolscin was used as a radiolabeled ligand for binding to α _2A -, α _2B -, α _2C - receptors and Chinese hamster ovary (CHO) cells expressing cloned human α _2A -, α _2B - and α _{2C were} used as a receptor preparation - receptors.

Among the tested compounds, compounds No. 1, 5, 7, 8, 11, 12, 13, 16, 17, 19, 24, 28, 29, 20, 32, 33, and 36 inhibited each of the three receptors by more than 50% in the tested concentration varying from 10 ^-6 to 10 ^-9 M.

D. Examples of compositions

The "active ingredient" (A. I.) used in all of these examples refers to a compound of formula (I), a pharmaceutically acceptable addition salt thereof, or a stereochemically isomeric form.

Example D.1: Capsules

20 g of A.I., 6 g of sodium lauryl sulfate, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide and 1.2 g of magnesium stearate are intensively mixed together. The resulting mixture was subsequently filled in 1000 suitable hard gelatin capsules, each containing 20 mg A.I.

Example D.2: Film Coated Tablets

Getting the core of the pill

A mixture of 100 g A.I., 570 g lactose and 200 g starch is mixed well and then moistened with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone in approximately 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then add 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil. All together well mixed and pressed into tablets, receiving 10,000 tablets, each of which contains 10 mg of the active ingredient.

Coating

To a solution of 10 g methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane.

Then add 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The last solution is added to the first and then 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated colored suspension are added, and all are homogenized together. The tablet cores are coated with the mixture thus obtained in a coating device.

Example D.3: Oral Solution

9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate are dissolved in 4 l of boiling purified water. First, 10 g of 2,3-dihydroxybutanedioic acid and then 20 g of A. are dissolved in 3 L of this solution. I. The last solution is combined with the remaining part of the first solution and then 12 L of 1,2,3-propanetriol and 3 L of 70% sorbitol solution are added. . 40 g of sodium saccharin are dissolved in 0.5 l of water and 2 ml of raspberry and 2 ml of gooseberry essence are added. The last solution is combined with the first, water is added in an amount sufficient to obtain a volume of 20 l, obtaining a solution for oral administration containing 5 mg of the active ingredient per teaspoon (5 ml). The resulting solution is filled in suitable containers.

Example D.4: Injection

1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate are dissolved in approximately 0.5 l of boiling water for injection. After cooling to approximately 50 ° C., 4 g of lactic acid, 0.05 g of propylene glycol and 4 g of A. are added with stirring. I. The solution is cooled to RT and water for injection is added in an amount sufficient to obtain a volume of 1 l, obtaining a solution containing 4 mg / ml A.I. The solution is sterilized by filtration and filled with sterile containers.

The results are given in table. 2, 3.

Claims (12)

1. Tricyclic Δ3-piperidines of the formula (I)

its N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form, in said formula Alk is C _1-6 alkanediyl; n is 0 or 1; X ₁ represents —O— or —S—; each R ¹ substituting a hydrogen atom attached to an aromatic ring independently represents halogen, C _1-6 alkyl or C _1-4 alkyloxy; D represents a radical of the formula

in which each m is independently 0 or 1; X ₂ represents —NR ¹¹ -; X ₃ represents —S—; X ₄ represents —NR ¹² -; X ₅ is —O— or —S—; R ² represents C _1-6 alkyl, aryl or aryl C _1-6 alkyl; R ³ and R ⁴ taken together can form a bivalent radical —R ³ —R ⁴ —formulas —CH═CH — CH═CH— (a-5) or —S-CH = CH- (a-8); R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ each independently represents hydrogen or C _1-6 alkyl; R ¹² is C _1-6 alkyloxyC _1-6 alkyl or piridinilC _1-6 alkyl; R ¹³ represents halogen; aryl is phenyl or phenyl substituted with halogen or C _1-6 alkyl. 2. The compound according to claim 1, in which D represents a radical of the formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j) or (k) in which m is 0; and aryl is phenyl or phenyl substituted with halogen or C _1-6 alkyl. 3. The compound according to claim 1 or 2, in which n is 1, and R ¹ represents hydrogen, chlorine, fluorine, methyl, methoxy. 4. The compound according to any one of claims 1 to 3, in which Alk is methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl or 1,5-pentanediyl. 5. The compound according to any one of claims 1 to 4, in which D represents a radical of formula (a), in which R ² represents aryl or methyl, and R ³ and R ⁴ taken together form a bivalent radical of formula (a-5) or (a-8); or D represents a radical of formula (b) in which R ⁵ and R ⁶ are C _1-6 alkyl; or D represents a radical of formula (c) in which R ⁷ represents hydrogen; or D represents a radical of formula (d) in which X ₂ represents —NR ¹¹ - and R ¹¹ represents hydrogen; or D represents a radical of formula (e); or D represents a radical of formula (f) in which X ₃ is —S— and R ⁸ is hydrogen or C _1-6 alkyl; or D represents a radical of formula (g) in which X ₄ is —NR ¹² - and R ¹² is C _1-6 alkyloxy C _1-6 alkyl or pyridinyl C _1-6 alkyl; or D represents a radical of formula (h) in which X ₅ is —O— or —S—, and R ¹⁰ is hydrogen; or D represents a radical of formula (i) in which R ⁹ represents methyl; or D represents a radical of formula (j); or D represents a radical of formula (k) in which m is 1, and R ¹³ is halogen. 6. The compound according to claim 1, which represents

or its N-oxide form, a pharmaceutically acceptable addition salt, or a stereochemically isomeric form. 7. The compound according to any one of claims 1 to 6, useful as an antagonist of α ₂ -adrenoreceptors. 8. The compound according to any one of claims 1 to 5, suitable in the manufacture of medicaments for the treatment of depression or Parkinson's disease. 9. A pharmaceutical composition for treating diseases in which antagonistic activity towards a central α ₂ -adrenoreceptor is shown, comprising as a active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier. 10. The method of producing the compound according to claim 1, characterized in that it includes N-alkylation of an intermediate of the formula (II):

where X ₁ , n and R ¹ have the meanings defined in claim 1, an alkylating reagent of formula (III): D-Alk-W ¹ , where W ¹ represents a suitable leaving group, and D, Alk have the meanings defined in claim 1, in a solvent inert to the reaction, in the presence of a base and optionally in the presence of a catalyst to obtain a compound of formula (I); and, optionally, converting the compounds of formula (I) into each other using transformations known in the art, and then, if desired, converting the compounds of formula (I) into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active a non-toxic base addition salt by treatment with a base, or, conversely, conversion of the acid addition salt form to the free base by treatment with alkali, or conversion of the base addition salt into the free acid by treatment with acids th; and, if desired, the preparation of their stereochemically isomeric forms or N-oxides. 11. The method of obtaining the compounds of formula (I) according to claim 1, which is a compound of formula (I-f)

in which X ₃ , X ₁ , Alk, R ¹ R ⁸ and n are as defined in claim 1, characterized in that it includes N-alkylation of an amine of the formula (IV)

where Alk, X ₁ , n, R ¹ and R ⁸ have the meanings defined in claim 1, by an intermediate of formula (V)

where W ² represents a suitable leaving group, and X ₃ has the meanings defined in claim 1, with the formation, thus, the compounds of formula (If); and optionally, converting the compounds of formula (I) into each other using transformations known in the art, and then, if desired, converting the compounds of formula (I) into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or, conversely, conversion of an acid addition salt form to a free base by treatment with alkali, or conversion of a base addition salt of a base into free acid by treatment with an acid th; and, if desired, the preparation of their stereochemically isomeric forms or N-oxides. 12. The method of obtaining the compounds of formula (I) according to claim 1, which is a compound of formula (I-j)

in which Alk 'represents C _1-5 alkanediyl; X ₁ , n, R ¹ have the meanings defined in claim 1, characterized in that it includes reductive N-alkylation of an intermediate of formula (II)

in which X ₁ , R ¹ and n have the meanings defined in claim 1, aldehyde derivative of the formula (VI)

in which Alk ’has the meanings indicated above, p is 0 or 1, by reducing the reagent mixture in a suitable reaction inert solvent, in accordance with techniques known in the art for reductive N-alkylation, to form a compound of formula (I-j); and, optionally, converting the compounds of formula (I) into each other using transformations known in the art, and then, if desired, converting the compounds of formula (I) into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active a non-toxic base addition salt by treatment with a base, or, conversely, conversion of the acid addition salt form to the free base by treatment with alkali, or conversion of the base addition salt into the free acid by treatment with acids th; and, if desired, the preparation of their stereochemically isomeric forms or N-oxides.